Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence

Molecular Psychiatry volume 14, pages 501–510 (2009)Cite this article

Abstract

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3′-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5–CHRNA3–CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Istvan J, Matarazzo JD . Tobacco, alcohol, and caffeine use: a review of their interrelationships. Psychol Bull 1984; 95: 301–326.

    Article  CAS  Google Scholar 

  2. Marks JL, Hill EM, Pomerleau CS, Mudd SA, Blow FC . Nicotine dependence and withdrawal in alcoholic and nonalcoholic ever-smokers. J Subst Abuse Treat 1997; 14: 521–527.

    Article  CAS  Google Scholar 

  3. Daeppen JB, Smith TL, Danko GP, Gordon L, Landi NA, Nurnberger Jr JI et al. Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. The Collaborative Study Group on the Genetics of Alcoholism. Alcohol Alcohol 2000; 35: 171–175.

    Article  CAS  Google Scholar 

  4. John U, Meyer C, Rumpf HJ, Hapke U . Probabilities of alcohol high-risk drinking, abuse or dependence estimated on grounds of tobacco smoking and nicotine dependence. Addiction 2003; 98: 805–814.

    Article  Google Scholar 

  5. John U, Meyer C, Rumpf HJ, Schumann A, Thyrian JR, Hapke U . Strength of the relationship between tobacco smoking, nicotine dependence and the severity of alcohol dependence syndrome criteria in a population-based sample. Alcohol Alcohol 2003; 38: 606–612.

    Article  Google Scholar 

  6. Grant BF . Age at smoking onset and its association with alcohol consumption and DSM-IV alcohol abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse 1998; 10: 59–73.

    Article  CAS  Google Scholar 

  7. Heath AC, Bucholz KK, Madden PA, Dinwiddie SH, Slutske WS, Bierut LJ et al. Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychol Med 1997; 27: 1381–1396.

    Article  CAS  Google Scholar 

  8. True WR, Heath AC, Scherrer JF, Waterman B, Goldberg J, Lin N et al. Genetic and environmental contributions to smoking. Addiction 1997; 92: 1277–1287.

    Article  CAS  Google Scholar 

  9. True WR, Xian H, Scherrer JF, Madden PA, Bucholz KK, Heath AC et al. Common genetic vulnerability for nicotine and alcohol dependence in men. Arch Gen Psychiatry 1999; 56: 655–661.

    Article  CAS  Google Scholar 

  10. Bierut LJ, Schuckit MA, Hesselbrock V, Reich T . Co-occurring risk factors for alcohol dependence and habitual smoking. Alcohol Res Health 2000; 24: 233–241.

    CAS  PubMed  Google Scholar 

  11. Grucza RA, Bierut LJ . Co-occurring risk factors for alcohol dependence and habitual smoking: update on findings from the Collaborative Study on the Genetics of Alcoholism. Alcohol Res Health 2006; 29: 172–178.

    Google Scholar 

  12. Kendler KS, Neale MC, Sullivan P, Corey LA, Gardner CO, Prescott CA . A population-based twin study in women of smoking initiation and nicotine dependence. Psychol Med 1999; 29: 299–308.

    Article  CAS  Google Scholar 

  13. Prescott CA, Kendler KS . Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 1999; 156: 34–40.

    Article  CAS  Google Scholar 

  14. Madden PA, Heath AC . Shared genetic vulnerability in alcohol and cigarette use and dependence. Alcohol Clin Exp Res 2002; 26: 1919–1921.

    Article  Google Scholar 

  15. Aistrup GL, Marszalec W, Narahashi T . Ethanol modulation of nicotinic acetylcholine receptor currents in cultured cortical neurons. Mol Pharmacol 1999; 55: 39–49.

    Article  CAS  Google Scholar 

  16. Cardoso RA, Brozowski SJ, Chavez-Noriega LE, Harpold M, Valenzuela CF, Harris RA . Effects of ethanol on recombinant human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 1999; 289: 774–780.

    CAS  Google Scholar 

  17. Larsson A, Engel JA . Neurochemical and behavioral studies on ethanol and nicotine interactions. Neurosci Biobehav Rev 2004; 27: 713–720.

    Article  CAS  Google Scholar 

  18. Butt CM, King NM, Stitzel JA, Collins AC . Interaction of the nicotinic cholinergic system with ethanol withdrawal. J Pharmacol Exp Ther 2004; 308: 591–599.

    Article  CAS  Google Scholar 

  19. Gotti C, Fornasari D, Clementi F . Human neuronal nicotinic receptors. Prog Neurobiol 1997; 53: 199–237.

    Article  CAS  Google Scholar 

  20. Lindstrom JM . Nicotinic acetylcholine receptors of muscles and nerves: comparison of their structures, functional roles, and vulnerability to pathology. Ann N Y Acad Sci 2003; 998: 41–52.

    Article  CAS  Google Scholar 

  21. Davis TJ, de Fiebre CM . Alcohol’s actions on neuronal nicotinic acetylcholine receptors. Alcohol Res Health 2006; 29: 179–185.

    PubMed  Google Scholar 

  22. Feng Y, Niu T, Xing H, Xu X, Chen C, Peng S et al. A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men. Am J Hum Genet 2004; 75: 112–121.

    Article  CAS  Google Scholar 

  23. Li MD, Beuten J, Ma JZ, Payne TJ, Lou XY, Garcia V et al. Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet 2005; 14: 1211–1219.

    Article  CAS  Google Scholar 

  24. Ehringer MA, Clegg HV, Collins AC, Corley RP, Crowley T, Hewitt JK et al. Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 596–604.

    Article  Google Scholar 

  25. Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau OF et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 2007; 16: 24–35.

    Article  CAS  Google Scholar 

  26. Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 2007; 16: 36–49.

    Article  CAS  Google Scholar 

  27. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd edn. (revised) American Psychiatric Press: Washington, DC, 1987.

  28. Feighner JP, Robins E, Guze SB, Woodruff Jr RA, Winokur G, Munoz R . Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 1972; 26: 57–63.

    Article  CAS  Google Scholar 

  29. Nurnberger Jr JI, Wiegand R, Bucholz K, O’Connor S, Meyer ET, Reich T et al. A family study of alcohol dependence: coaggregation of multiple disorders in relatives of alcohol-dependent probands. Arch Gen Psychiatry 2004; 61: 1246–1256.

    Article  Google Scholar 

  30. Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, Van Eerdewegh P et al. Genome-wide search for genes affecting the risk for alcohol dependence. Am J Med Genet 1998; 81: 207–215.

    Article  CAS  Google Scholar 

  31. Bucholz KK, Cadoret R, Cloninger CR, Dinwiddie SH, Hesselbrock VM, Nurnberger Jr JI et al. A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA. J Stud Alcohol 1994; 55: 149–158.

    Article  CAS  Google Scholar 

  32. Hesselbrock M, Easton C, Bucholz KK, Schuckit M, Hesselbrock V . A validity study of the SSAGA—a comparison with the SCAN. Addiction 1999; 94: 1361–1370.

    Article  CAS  Google Scholar 

  33. Barrett JC FB, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  Google Scholar 

  34. Laird NM, Horvath S, Xu X . Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000; 19 (Suppl 1): S36–S42.

    Article  Google Scholar 

  35. Horvath S, Xu X, Laird NM . The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 2001; 9: 301–306.

    Article  CAS  Google Scholar 

  36. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Rabinowitz D, Laird N . A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000; 50: 211–223.

    Article  CAS  Google Scholar 

  38. Lazzeroni LC, Lange K . A conditional inference framework for extending the transmission/disequilibrium test. Hum Hered 1998; 48: 67–81.

    Article  CAS  Google Scholar 

  39. Storey JD . A direct approach to false discovery rates. J R Stat Soc B 2002; 64: 479–498.

    Article  Google Scholar 

  40. Bierut LJ, Strickland JR, Thompson JR, Afful SE, Cottler LB . Drug use and dependence in cocaine dependent subjects, community-based individuals, and their siblings. Drug Alcohol Depend 2008; 95: 14–22.

    Article  Google Scholar 

  41. Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–221.

    Article  Google Scholar 

  42. Hosmer DW, Lemeshow S . Applied Logistic Regression. Wiley: New York, 1989.

    Google Scholar 

  43. Muller PY, Janovjak H, Miserez AR, Dobbie Z . Processing of gene expression data generated by quantitative real-time RT-PCR. Biotechniques 2002; 32: 1372–1374, 1376, 1378–1379.

    CAS  PubMed  Google Scholar 

  44. Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X et al. Variants in the nicotinic receptors alter the risk for nicotine dependence. Am J Psychiatry 2008; in press.

  45. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS et al. Genetic analysis of genome-wide variation in human gene expression. Nature 2004; 430: 743–747.

    Article  CAS  Google Scholar 

  46. Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, Burdick JT . Mapping determinants of human gene expression by regional and genome-wide association. Nature 2005; 437: 1365–1369.

    Article  CAS  Google Scholar 

  47. Flora A, Schulz R, Benfante R, Battaglioli E, Terzano S, Clementi F et al. Transcriptional regulation of the human alpha5 nicotinic receptor subunit gene in neuronal and non-neuronal tissues. Eur J Pharmacol 2000; 393: 85–95.

    Article  CAS  Google Scholar 

  48. Flora A, Schulz R, Benfante R, Battaglioli E, Terzano S, Clementi F et al. Neuronal and extraneuronal expression and regulation of the human alpha5 nicotinic receptor subunit gene. J Neurochem 2000; 75: 18–27.

    Article  CAS  Google Scholar 

  49. Buckland PR, Hoogendoorn B, Coleman SL, Guy CA, Smith SK, O’Donovan MC . Strong bias in the location of functional promoter polymorphisms. Hum Mutat 2005; 26: 214–223.

    Article  CAS  Google Scholar 

  50. Nashmi R, Lester HA . CNS localization of neuronal nicotinic receptors. J Mol Neurosci 2006; 30: 181–184.

    Article  CAS  Google Scholar 

  51. Gotti C, Clementi F . Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 2004; 74: 363–396.

    Article  CAS  Google Scholar 

  52. Gerzanich V, Wang F, Kuryatov A, Lindstrom J . Alpha 5 Subunit alters desensitization, pharmacology, Ca++ permeability and Ca++ modulation of human neuronal alpha 3 nicotinic receptors. J Pharmacol Exp Ther 1998; 286: 311–320.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The Collaborative Study on the Genetics of Alcoholism (COGA)—co-principal investigators B Porjesz, V Hesselbrock, H Edenberg, L Bierut—includes nine different centers where data collection, analysis and storage take place. The nine sites and principal investigators and co-investigators are University of Connecticut (V Hesselbrock), Indiana University (HJ Edenberg, J Nurnberger Jr, PM Conneally, T Foroud), University of Iowa (S Kuperman, R Crowe), SUNY Downstate (B Porjesz), Washington University in St Louis (L Bierut, A Goate, J Rice), University of California at San Diego (M Schuckit), Howard University (R Taylor), Rutgers University (J Tischfield), Southwest Foundation (L Almasy). Zhaoxia Ren serves as the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA008401 from the NIAAA and the National Institute on Drug Abuse (NIDA).

In memory of Henri Begleiter and Theodore Reich, Principal and co-principal investigators of COGA since its inception; we are indebted to their leadership in the establishment and nurturing of COGA, and acknowledge with great admiration their seminal scientific contributions to the field.

We are grateful to the families for their participation in the studies at St Louis Alzheimer's Disease Research Center (ADRC), Washington University. Funding for the research at ADRC was provided by grants from the National Institute on Aging: P50 AG05681 and P01 AG03991 to John C Morris. The Family Study of Cocaine Dependence (FSCD) data collection was funded by the National Institute of Drug Abuse (NIDA), R01 DA13423 to Laura J Bierut. Genotyping and analysis of the FSCD data was supported through the Case Control Candidate Gene Study of Addiction, NIDA grant R01 DA19963 to Laura J Bierut.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA

    J C Wang, R Grucza, C Cruchaga, A L Hinrichs, S Bertelsen, J P Budde, L Fox, E Goldstein, O Reyes, S Saccone, K Bucholz, J P Rice, L J Bierut & A M Goate

  2. Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA

    N Saccone & A M Goate

  3. Department of Biochemistry and Molecular Genetics, Indiana University, Indianapolis, IN, USA

    X Xuei & H J Edenberg

  4. Division of Child Psychiatry, University of Iowa, Iowa City, IA, USA

    S Kuperman

  5. Department of Psychiatry, Indiana University, Indianapolis, IN, USA

    J Nurnberger Jr

  6. Department of Psychiatry, San Diego VA Medical Center, UCSD, San Diego, CA, USA

    M Schuckit

  7. Department of Genetics/HGI, Rutgers University, Piscataway, NJ, USA

    J Tischfield

  8. Department of Psychiatry, University of Connecticut, Farmington, CT, USA

    V Hesselbrock

  9. Department of Psychiatry, SUNY Health Science Center, Brooklyn, NY, USA

    B Porjesz

  10. Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA

    A M Goate

Authors
  1. J C Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Grucza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Cruchaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A L Hinrichs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Bertelsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J P Budde
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. O Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N Saccone
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Saccone
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. X Xuei
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K Bucholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. S Kuperman
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J Nurnberger Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J P Rice
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M Schuckit
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. J Tischfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. V Hesselbrock
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. B Porjesz
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. H J Edenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. L J Bierut
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. A M Goate
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A M Goate.

Additional information

Financial Disclosures:

Drs LJ Bierut, AM Goate, AJ Hinrichs, JP Rice, SF Saccone and JC Wang are listed as inventors on a patent (US 20070258898) held by Perlegen Sciences Inc., covering the use of certain SNPs, including rs16969968 in diagnosing, prognosing and treating addiction. Dr Bierut has acted as a consultant for Pfizer Inc. in 2008.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, J., Grucza, R., Cruchaga, C. et al. Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol Psychiatry 14, 501–510 (2009). https://doi.org/10.1038/mp.2008.42

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.42

Keywords

This article is cited by

Search

Advanced search

Quick links